HPT1

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HPT1 (human peptide transporter 1)

Aliases: CDH16, CDH17
Gene name: Cadherin 17, LI cadherin (liver-intestine) (CDH17)

Summary

The human intestinal peptide transporter 1 (HPT1) is more correctly known as cadherin-17 (CDH17) or LI cadherin (Liver Intestine cadherin). It is not a typical drug transporter in that it is a member of the cadherin superfamily of genes encoding calcium-dependent, membrane-associated glycoproteins, and it is unrelated to the ABC or SLC transporter superfamilies. However, it has been identified as a bi-directional, proton-dependent oligopeptide transporter in the gastrointestinal tract (GIT) with valacyclovir as a verified substrate, and it is expressed in Caco-2 cells. Therefore, it may be of importance in the oral absorption of similar peptide-like drugs, although this has not been fully investigated. The protein is predominantly expressed in the GIT.
As it is not documented as a transporter with significant drug interaction liabilities, neither the FDA nor the EMA guidances make any comment on this transporter.

Localization

HPT1 was first identified among Caco-2 membrane proteins where it has been shown to facilitate transport across the cell monolayer [1]. Subsequently, this transporter was identified in human and rat tissues [2]. HPT1 mRNA is widely expressed along the human GIT. There is no expression in the esophagus, and expression increases from the stomach to the ileocecum with highest expression along the length of the colon [2]. HPT1 is present in fetal liver and gastrointestinal tract during embryogenesis, but the gene becomes silenced in healthy adult liver and stomach tissues [3]. When comparing HPT1 expression in mouse, rat, and human intestine, HPT1 was detected in both human and mouse intestinal tissues with more than double the expression in human, while only very low levels were detected in the rat [4].
HPT1 is apically expressed in Caco-2 cells [5].

Function, physiology and clinically significant polymorphisms

HPT1 is a 832-amino acid proton-dependent peptide transporter belonging to a subclass of the 7D-cadherin superfamily [5]. HPT1 is also implicated in the morphological organization of the liver and intestine [6], where as a Ca2+-dependent cell-cell adhesion molecule it helps to maintain epithelial tissue integrity. Although it has been reported to play a role in the oral absorption of certain peptide-based drugs, HPT1 exhibits only 16% identity and 41% similarity in amino acid sequence with the established peptide transporter PEPT1 [7], and its exact function as a transporter remains incompletely defined [8].
Dysregulation of cadherin expression has been associated with disease pathology including tissue dysplasia, tumor formation and metastasis. Aberrant expression of CDH17 has been reported in major gastrointestinal malignancies including hepatocellular carcinoma (HCC), stomach and colorectal cancers. HPT1 is associated with tumor metastasis and advanced tumors. Alternative splice isoforms and genetic polymorphisms of CDH17 gene have been identified in HCC and linked to an increased risk of this carcinoma. CDH17 is an attractive target for HCC therapy [3].

Clinical significance

Valacyclovir, a drug used for the treatment of herpes, is a substrate for HPT1 and PEPT1 [9, 10], and these transporters are effective in the oral absorption of this drug in humans. While there are several other peptide drugs on the market, these have not been fully evaluated as substrates or inhibitors of HPT1. Therefore, there has been no systematic evaluation of the clinical relevance of HTP1 in drug absorption and DDIs.

Regulatory Requirements

As the information on the clinical relevance of HPT1 is scant, it does not merit a mention in the FDA or EMA guidances.


References


1.    Herrera-Ruiz, D. and G.T. Knipp, Current perspectives on established and putative mammalian oligopeptide transporters. Journal of Pharmaceutical Sciences, 2003. 92(4): p. 691-714.
2.    Herrera-Ruiz, D., et al., Spatial expression patterns of peptide transporters in the human and rat gastrointestinal tracts, Caco-2 in vitro cell culture model, and multiple human tissues. AAPS PharmSci, 2001. 3(1): p. E9.
3.    Lee, N.P., et al., Role of cadherin-17 in oncogenesis and potential therapeutic implications in hepatocellular carcinoma. Biochimica et Biophysica Acta, 2010. 1806(2): p. 138-45.
4.    Kim, H.R., et al., Comparative gene expression profiles of intestinal transporters in mice, rats and humans. Pharmacological Research, 2007. 56(3): p. 224-36.
5.    Dantzig, A.H., et al., Association of intestinal peptide transport with a protein related to the cadherin superfamily. Science, 1994. 264(5157): p. 430-3.
6.    Yang, C.Y., A.H. Dantzig, and C. Pidgeon, Intestinal peptide transport systems and oral drug availability. Pharmaceutical Research, 1999. 16(9): p. 1331-43.
7.    Liang, R., et al., Human intestinal H+/peptide cotransporter. Cloning, functional expression, and chromosomal localization. Journal of Biological Chemistry, 1995. 270(12): p. 6456-63.
8.    Baumgartner, W., Possible roles of LI-Cadherin in the formation and maintenance of the intestinal epithelial barrier. Tissue Barriers, 2013. 1(1): p. e23815.
9.    Landowski, C.P., et al., Gene expression in the human intestine and correlation with oral valacyclovir pharmacokinetic parameters. Journal of Pharmacology and Experimental Therapeutics, 2003. 306(2): p. 778-86.
10.    Bolger, M.B., V. Lukacova, and W.S. Woltosz, Simulations of the nonlinear dose dependence for substrates of influx and efflux transporters in the human intestine. AAPS Journal, 2009. 11(2): p. 353-63.

 

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